The cardiovascular diseases, such as myocardial infarction and cerebrovascular disorder, are the main cause of death, along with malignant tumors. Patients of heart failure which is the terminal state of these cardiovascular diseases, have substantially increased, and the number of such patients exceeds 1 million because of population aging, increased lifestyle-related disease causing heart failure, spread of acute stage therapy as well as improvement of treatment results in myocardial infarction, and the like.
By recent advances in drug therapy and non-drug therapy, prognosis of heart failure patients has been greatly improved. However, prognosis of severe cases is still poor even with these various therapies against heart failure, and patients in severe cases repeat hospitalizations due to its exacerbation, finally resulting in death. Therefore, there is a great need for development of a new therapeutic method for cardiovascular diseases, including myocardial infarction and heart failure.
Natural killer T (NKT) cells are a unique subset of T lymphocytes that simultaneously express NK cell markers and T cell receptors. Their T cell receptor has invariant α-chain, which is Vα14-Jα18 in mice and Vα24-Jα18 in humans. NKT cells are activated by recognizing glycolipid antigens presented by CD1d molecule that is an MHC class I-like molecule. The activated NKT cells rapidly produce large amounts of T helper (Th) type 1-cytokines of which representatives are interferon (IFN)-γ and tumor necrosis factor (TNF)-α, or Th2-type cytokines of which representatives are interleukins IL-4 and IL-10 in shaping subsequent adaptive immune response. Thus, NKT cells are believed to function as a bridge between the innate and adaptive immune system and to orchestrate tissue inflammation (Non-Patent Literature 1).
Although endogenous ligands of NKT cells have not become clear yet, α-galactosylceramide (α-GalCer) is known to specifically activate NKT cells (Non-Patent Literature 2), and many studies of NKT cells using α-GalCer have been reported. In the past animal experiments, it was reported that type 1 diabetes, autoimmune encephalomyelitis, rheumatoid arthritis, enteritis, and hepatic ischemia-reperfusion injury were improved by the administration of α-GalCer (Non-Patent Literatures 3 to 7). In addition, the present inventors have confirmed the therapeutic effects by systemic administration of α-GalCer in post-myocardial infarction heart failure models, cardiac ischemia-reperfusion injury models, and abdominal aortic aneurysm models (Non-Patent Literatures 8 to 10).
Such study results support the possibility that the activation of NKT cells by α-GalCer provides a new therapeutic method for cardiovascular diseases. However, clinical application of α-GalCer was difficult because the activation of NKT cells by α-GalCer was transient, the efficacy of α-GalCer was lowered when it was repeatedly administered, and the systemic administration of α-GalCer caused a liver damage.
In recent years, a technique of NKT cell activation by dendritic cells pulsed with α-GalCer has been developed (Non-Patent Literature 11), and clinical trials for lung cancer, and head and neck cancer were performed (Non-Patent Literature 12).
In cellular immunotherapy using NKT cells, control of the direction of the immune response of NKT cells affects the success of treatment. That is, when the diseases to be treated are those in which Th1-type cytokines are known to be therapeutically effective, such as cancers and infections, it is necessary to shift the immune response of NKT cells toward Th1 type. For example, in the clinical trials for lung cancer, and head and neck cancer mentioned above, a remarkable increase in the expression of IFN-γ, which is a Th1-type cytokine, is observed in the NKT cells used.
On the other hand, when the diseases to be treated are autoimmune disease, graft versus host disease and the like, it is necessary to shift the immune response of NKT cells toward Th2 type. For example, in an experimental autoimmune encephalomyelitis model, the condition was improved by the administration of antigen presenting cells treated with α-GalCer and anti-CD86 antibody to shift toward Th2 type (Non-Patent Literature 13).
Non-Patent Literature 13 has also revealed that the condition turns worse adversely by the administration of antigen presenting cells treated with α-GalCer and anti-CD40 antibody to shift toward Th1 type. This suggests that the control of immune responses of NKT cells is very important in the treatment of diseases and its improper control adversely exacerbates the disease.
For the treatment of cardiovascular diseases, it is important to induce NKT cells into the direction to produce Th2-type cytokines, mainly IL-10 (Non-Patent Literatures 8 to 10). Conventional methods for preparing α-GalCer-pulsed dendritic cells having an ability to shift the NKT cells toward Th2 type include, for example, a method of pulsing dendritic cells with an α-GalCer derivative as described in Patent Literature 1 in addition to the method using an anti-CD86 antibody described above, but such methods are not sufficient from the viewpoint of clinical applications, such as efficacy and safety.